Involvement In Depression Research Articles

P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol

Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms. Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade. Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling. Depression and stress response can be alleviated by Cannabidiol (CBD). CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD's effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons. This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.

Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits

BackgroundN-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear. MethodsFirstly, expression of GluN3A was examined in a mouse model of depression induced by chronic restraint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting. ResultsGluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression. LimitationsThe mechanism underlying GluN3A involvement in depression is not fully determined. ConclusionsOur data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs.

Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients

Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.

Imaging synaptic density in depression.

Major depressive disorder is a prevalent and heterogeneous disorder with treatment resistance in at least 50% of individuals. Most of the initial studies focused on the monoamine system; however, recently other mechanisms have come under investigation. Specific to the current issue, studies show synaptic involvement in depression. Other articles in this issue report on reductions in synaptic density, dendritic spines, boutons and glia associated with stress and depression. Importantly, it appears that some drugs (e.g., ketamine) may lead to rapid synaptic restoration or synaptogenesis. Direct evidence for this comes from preclinical work. However, neuroimaging studies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have become useful in assessing these changes in vivo. Here, we describe the use of neuroimaging techniques in the evaluation of synaptic alterations associated with depression in humans, as well as measurement of synaptic restoration after administration of ketamine. Although more research is desired, use of these techniques widen our understanding of depression and move us further along the path to targeted and effective treatment for depression.

Association Between Self-rating Depression Scores and Total Ghrelin and Adipokine Serum Levels in a Large Population-Based Sample.

BackgroundGhrelin and the adipokines leptin and adiponectin have been suggested to be involved in mood and anxiety regulation and to be altered in affective disorders. However, studies investigating the association between ghrelin, leptin and adiponectin and depressive symptomatology are scarce but might contribute to a better understanding of their involvement in mood regulation. We thus aimed investigating the association between depressive symptomatology and total ghrelin as well as leptin and adiponectin serum levels in a large population-based sample.MethodsTotal serum ghrelin, adiponectin and leptin levels were determined in 1666 subjects of a population-based cross-sectional study (“LIFE”). The Center for Epidemiological Studies Depression Scale (CES-D) and the Inventory of Depressive Symptoms – Self Rating (IDS-SR) were administered. Multiple linear regression analyses were conducted to examine the association between total serum ghrelin, leptin and adiponectin and the intensity of depressive symptoms.ResultsIn the total sample (n = 1,092), neither ghrelin nor leptin or adiponectin serum levels showed a significant association with CES-D or IDS-SR sum scores (N = 1,092) or in depressed/non-depressed subjects. Leptin serum levels showed a significantly positive association with IDS-SR sum scores in elderly men (≥60 years; β = 0.122, 95% CI: 0.009; 0.236; p = 0.035).ConclusionOur study suggests that peripheral levels of ghrelin and adipokines in a cross-sectional study design might not be sufficient to measure their involvement in depression, suggesting that associations are more complex and multi-layered.

Inverse Association Between Persistence With Antidepressant Medication and Onset of Chronic Pain in Patients With Depression: A Retrospective Cohort Study.

Despite the known involvement of depression in chronic pain, the association between persistence with and adherence to antidepressant medication and onset of chronic pain in patients with depression remains unclear. This retrospective cohort study used a Japanese claims database to extract data for adult patients with depression who were prescribed antidepressants between April 2014 and March 2020. Patients were divided into groups according to duration of continuous prescription of antidepressants (≥6 months [persistent group] and <6 months [nonpersistent group]) and medication possession ratio (≥80% [good adherence group] and <80% [poor adherence group]). The outcome was onset of chronic pain, which was defined as continuous prescription >3 months of analgesics and diagnosis of pain-related condition after discontinuation of the first continuous antidepressant prescription. The risk of onset of chronic pain was compared between the paired groups. A total of 1859 patients were selected as the study population and categorized as the persistent (n = 406) and nonpersistent (n = 1453) groups, and good adherence (n = 1551) and poor adherence (n = 308) groups. Risk of onset of chronic pain was significantly lower in the persistent group than in the nonpersistent group after controlling for confounding via standardized mortality ratio weighting (hazard ratio, 0.38; 95% confidence interval, 0.18-0.80; P = 0.011). There was no significant difference between the good and poor adherence groups. Antidepressant persistence for ≥6 months is recommended and may reduce the onset of chronic pain in patients with depression.

Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells.

There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.

TRPA1 involvement in depression- and anxiety-like behaviors in a progressive multiple sclerosis model in mice

Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1β, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.

Anatomical and neurochemical organization of the serotonergic system in the mammalian brain and in particular the involvement of the dorsal raphe nucleus in relation to neurological diseases.

The brainstem is a neglected brain area in neurodegenerative diseases, including Alzheimer's and Parkinson's disease, frontotemporal lobar degeneration and autonomic dysfunction. In Depression, several observations have been made in relation to changes in one particular the Dorsal Raphe Nucleus (DRN) which also points toward as key area in various age-related and neurodevelopmental diseases. The DRN is further thought to be related to stress regulated processes and cognitive events. It is involved in neurodegeneration, e.g., amyloid plaques, neurofibrillary tangles, and impaired synaptic transmission in Alzheimer's disease as shown in our autopsy findings. The DRN is a phylogenetically old brain area, with projections that reach out to a large number of regions and nuclei of the central nervous system, particularly in the forebrain. These ascending projections contain multiple neurotransmitters. One of the main reasons for the past and current interest in the DRN is its involvement in depression, and its main transmitter serotonin. The DRN also points toward the increased importance and focus of the brainstem as key area in various age-related and neurodevelopmental diseases. This review describes the morphology, ascending projections and the complex neurotransmitter nature of the DRN, stressing its role as a key research target into the neural bases of depression.

Impaired Brain Energy Metabolism: Involvement in Depression and Hypothyroidism.

Although hypothyroidism appears to be an important factor in the pathogenesis of depression, the impact of thyroid hormones on the bioenergetics of the adult brain is still poorly known. Since metabolic changes are reported to be a key player in the manifestation of depressive disorder, we investigated whether there are differences in selected metabolic markers in the frontal cortex and hippocampus of Wistar Kyoto rats (WKY; an animal model of depression) compared to those of control Wistar rats and whether the induction of hypothyroidism by propylthiouracil (PTU) elicits similar effects in these animals or intensifies some parameters in the WKY rats. In our study, we used WKY rats as a model of depression since this strain exhibits lower levels of monoamines in the brain than control rats and exhibits behavioral and hormonal alterations resembling those of depression, including increased reactivity to stress. The findings indicate a decrease in glycolysis intensity in both brain structures in the WKY rats as well as in both strains under hypothyroidism conditions. Furthermore, hypothyroidism disrupted the connection between glycolysis and the Krebs cycle in the frontal cortex and hippocampus in the depression model used in this study. Decreased thyroid hormone action was also shown to attenuate oxidative phosphorylation, and this change was greater in the WKY rats. Our results suggest that both the depression and hypothyroidism models are characterized by similar impairments in brain energy metabolism and mitochondrial function and, additionally, that the co-occurrence of hypothyroidism and depression may exacerbate some of the metabolic changes observed in depression.

Bacterial Metabolites of Human Gut Microbiota Correlating with Depression.

Depression is a global threat to mental health that affects around 264 million people worldwide. Despite the considerable evolution in our understanding of the pathophysiology of depression, no reliable biomarkers that have contributed to objective diagnoses and clinical therapy currently exist. The discovery of the microbiota-gut-brain axis induced scientists to study the role of gut microbiota (GM) in the pathogenesis of depression. Over the last decade, many of studies were conducted in this field. The productions of metabolites and compounds with neuroactive and immunomodulatory properties among mechanisms such as the mediating effects of the GM on the brain, have been identified. This comprehensive review was focused on low molecular weight compounds implicated in depression as potential products of the GM. The other possible mechanisms of GM involvement in depression were presented, as well as changes in the composition of the microbiota of patients with depression. In conclusion, the therapeutic potential of functional foods and psychobiotics in relieving depression were considered. The described biomarkers associated with GM could potentially enhance the diagnostic criteria for depressive disorders in clinical practice and represent a potential future diagnostic tool based on metagenomic technologies for assessing the development of depressive disorders.

Role of School Bullying Involvement in Depression, Anxiety, Suicidality, and Low Self-Esteem Among Adolescents With High-Functioning Autism Spectrum Disorder.

This study aimed to compare the severities of psychopathologies and the level of self-esteem among 219 adolescents with high-functioning autism spectrum disorder (ASD) who were classified into pure perpetrators, pure victims, perpetrator-victims, and neutrals in Taiwan. The experiences of school bullying involvement in the previous 1 year were measured using the Chinese version of the School Bullying Experience Questionnaire. The severities of depression, anxiety, and suicidality were measured using the Center for Epidemiological Studies Depression Scale, the Multidimensional Anxiety Scale for Children, and the 5-item questionnaire from the epidemiological version of the Kiddie Schedule for Affective Disorders and Schizophrenia, respectively. The level of self-esteem was measured using the Rosenberg Self-Esteem Scale. The results indicated that compared with the self-reported neutrals, the self-reported perpetrator-victims and pure victims had more severe depression and anxiety. No difference in depression, suicidality, anxiety, and self-esteem was found among the four groups of various parent-reported bullying involvement experiences. Mental health problems in adolescents with ASD who experienced bullying victimization should be routinely surveyed.

Harmane suppresses microglial neuroinflammatory response and induce antidepressant-like effect in rats

ObjectiveHarmane is a beta-carboline, which binds to imidazoline receptors and it has been previously shown that it may have an antidepressant effect when administered acutely. This study is planned to investigate the effect of harmane on chronic unpredictable mild stress (CUMS) model and microglial (Iba-1) immunoreactivity in the same model as markers of neuroinflammation.MethodsMale Wistar Albino rats (290–360 g) were divided into groups such as control (saline), CUMS, CUMS + Imipramine (20 mg/kg; i.p.), CUMS + Harmane5 (5 mg/kg; i.p.), CUMS + Harmane10 (10 mg/kg; i.p.) groups (n = 10–12 in each). In CUMS model, various stressors were applied for 40 days. On day 20, harmane administration was started for 20 days. At the end, sucrose preference and forced swimming tests were performed. Then, brains were removed with paraformaldehyde perfusion for Iba-1 immunohistochemical analysis in hippocampus. One-way analysis of variance and Tukey's test were used for statistical analysis.ResultsThe time of immobility in forced swim test was significantly reduced while sucrose preference was increased in Imipramine and CUMS + harmane10 groups. In immunohistochemical experiments, Iba-1 were overexpressed in CUMS group and Harmane significantly reduced the overexpression of Iba-1.ConclusionOur results suggest that chronic administration of harmane has an antidepressant-like activity in chronic stress model of depression. These results support the notion of imidazoline receptors involvement in depression by modulating neuroinflammation and at least a part of its antidepressant effect might be through modulating microglial activation as a reflection of neuroinflammation.This research was supported by Marmara University, Scientific Research Projects – SAG-C-YLP-110915-0415 and SAG-E-120613-0233.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Beta Adrenoceptor Polymorphism and Clinical Response to Sertraline in Major Depressive Patients.

The adrenoceptor family, as one of the main contributors in regulating the noradrenergic system, has been studied in involvement of depression and its treatment. A functional polymorphism of G1165C on beta adrenoceptor (βAR) enhances post receptor signalling and is assumed to be involved in pharmacotherapy of depression. The aim of the present study was to discern the influence of G1165C polymorphism in the β1AR gene on individual differences in response to sertraline. One hundred newly diagnosed patients completed 6 weeks of sertraline treatment. Response to treatment was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD). The patients who carried CC genotype responded five times more to sertraline comparing with other variants (P=0.005; OR=5.7; 95%CI=1.4-23.9). Moreover, carriers of C allele responded three times more to sertraline than patients with the G allele (P=0.001; OR= 3.3; 95%CI= 1.72-6.50). In conclusion, our results support the hypothesis that genetic variation of β1AR might influence clinical response to sertraline.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Understanding alterations in serotonin connectivity in a rat model of depression within the monoamine-deficiency and the hippocampal-neurogenesis frameworks

The monoamine-deficiency and the hippocampal-neurogenesis hypotheses of depression propose that alterations in the serotonin system and of hippocampal functionality are critical in the pathogenesis of depression. We measured the alterations in the connectivity level of the raphe nucleus in the chronic mild stress (CMS) rat model of depression using the manganese enhanced MRI method (MEMRI). Manganese ions were injected into the median raphe and their anterograde intracellular propagation was followed. Depression-like behavior was demonstrated using the sucrose preference tests.We show that the raphe’s connectivity is differentially altered through chronic stress. In line with the monoamine-deficiency hypothesis, the connectivity of the raphe with the basal ganglia (BG) output nuclei, the hippocampus, the habenula and the entorhinal and insular cortices was reduced in CMS rats, suggesting an overall reduction in raphe excitability. Connectivity reductions were predominantly found in the right hemisphere, strengthening previous evidence pointing at a-symmetric hemispheric involvement in depression. Despite the general reduction in raphe connectivity, enhanced connectivity was found between the raphe and the septum, suggesting that alterations are connection-specific.On the basis of our results – while yet equivocal – we further discuss the possible coupling between the serotonergic and dopaminergic systems and two distinct mechanisms (direct and indirect) in which alterations in raphe connectivity may affect hippocampal dysfunction in chronic stress, thus linking the monoamine-deficiency and the hippocampal-neurogenesis hypotheses.

Testing a path model of relationships between gender, age, and bullying victimization and violent behavior, substance abuse, depression, suicidal ideation, and suicide attempts in adolescents

The goal of this study was to test a path model for the relationships between age, gender, traditional bullying and cyberbullying victimization, and violent behavior, substance abuse, depression, suicidal ideation and suicide attempts in adolescents. A hypothesized path model was fit to data from the 2011 Youth Risk Behavior Surveillance System (YRBSS) on a nationally representative sample of 15,425 high-school students from across the United States. Results suggested that the effects of traditional and cyberbullying victimization on suicidal thinking, suicide planning, and suicide attempts were mediated by violent behavior, substance abuse, and depression. Results also suggested reciprocal paths between substance abuse and violent behavior. There were statistically significant indirect paths from both traditional and cyberbullying victimization to suicide attempts without the involvement of depression, suicidal thinking, or suicide planning, findings suggesting a model for spontaneous, unplanned adolescent suicides. Results suggested that female adolescents who reported cyberbullying victimization also reported higher rates of depression and suicidal behaviors compared to their male counterparts, and that as adolescents got older, depression and substance abuse tended to increase, while violent behavior and suicidal thinking tended to decrease. The implications of these findings for social workers, school counselors, and others who work with adolescents are considered.

The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery.

Cytokines are implicated in the pathophysiology of major depressive disorder (MDD). However, the pattern of alterations in cytokine levels is still unclear. The current study investigated the plasma levels of a range of cytokines in a follow-up design, with the aim of determining their involvement in depression. Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed up after 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and blood for cytokine analysis was obtained. The same clinical assessments and cytokine measurements were performed after 12 weeks of "treatment as usual." The cytokines interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor (G-CSF), and interferon gamma (IFNγ) were significantly elevated (p=0.01-0.047) in depressed patients at baseline compared to healthy controls. After 12 weeks of treatment, the plasma levels of seven of these nine cytokines (IL-1Ra, IL-6, IL-7, IL-8, IL-10, G-CSF, and IFNγ had decreased significantly compared to baseline and did not differ from those in the healthy controls. The depressive symptoms were simultaneously significantly reduced. In addition, the reduction to normal cytokines levels occurred only in those who met the recovery criteria. A more general pattern of elevated cytokine levels is described herein relative to what has been described previously shown in MDD. Furthermore, recovery from depression was associated with reduction to normal levels of the majority of the measured cytokines. These results strongly support the notion that a complex network of cytokines is involved in the pathophysiology of MDD.

The Role of the Val66Met Polymorphism of the Brain Derived Neurotrophic Factor Gene in Coping Strategies Relevant to Depressive Symptoms.

Disturbances of brain derived neurotrophic factor (BDNF) signalling have been implicated in the evolution of depression, which likely arises, in part, as a result of diminished synaptic plasticity. Predictably, given stressor involvement in depression, BDNF is affected by recent stressors as well as stressors such as neglect experienced in early life. The effects of early life maltreatment in altering BDNF signalling may be particularly apparent among those individuals with specific BDNF polymorphisms. We examined whether polymorphisms of the Val66Met genotype might be influential in moderating how early-life events play out with respect to later coping styles, cognitive flexibility and depressive features. Among male and female undergraduate students (N = 124), childhood neglect was highly related to subsequent depressive symptoms. This outcome was moderated by the BDNF polymorphism in the sense that depressive symptoms appeared higher in Met carriers who reported low levels of neglect than in those with the Val/Val allele. However, under conditions of high neglect depressive symptoms only increased in the Val/Val individuals. In effect, the Met polymorphism was associated with depressive features, but did not interact with early life neglect in predicting later depressive features. It was further observed that among the Val/Val individuals, the relationship between neglect and depression was mediated by emotion-focused styles and diminished perceived control, whereas this mediation was not apparent in Met carriers. In contrast to the more typical view regarding this polymorphism, the data are consistent with the perspective that in the presence of synaptic plasticity presumably associated with the Val/Val genotype, neglect allows for the emergence of specific appraisal and coping styles, which are tied to depression. In the case of the reduced degree of neuroplasticity expected in the Met carriers, early life adverse experiences are not tied to coping styles, and hence less likely to be translated into depressive states.

The peripheral cerebrospinal fluid outflow pathway – physiology and pathophysiology of CSF recirculation: A review and hypothesis

An anatomical connection from subarachnoid spaces along nerves into peripheral tissues represents an important route for CNS antigens release, termed here peripheral cerebrospinal fluid outflow pathway (PCOP), is assumed analogous to mammals in humans: CSF leaves the subarachnoid spaces along nerves and joins respective interstitial tissue fluids, then the lymph then blood; in detail, flowing from the subfrontal subarachnoid spaces through the cribriform plate near olfactory nerves to nasal submucosa to the cervical lymph system, along cranial nerves and spinal nerves into respective peripheral tissues. Microanatomic details and relative shares of outflow volumes at various parts of the PCOP as compared to CSF reabsorption volumes into the venous system remain to be determined. Beyond, CSF functions as a third signaling system involving all CNS structures preferably surfaces, including spinal cord and nerve roots. But CSF may interact also with all cranial and peripheral nerves via the PCOP, and related peripheral tissues connected by nerves, e.g. subcutaneous tissues, muscles or neuronal ganglia, and even, a special case, the eye. PCOP associated pathomechanisms might arise with any abnormal pathogenic CSF contents including solutes and cells in various diseases, relevant especially in acute neuroinflammation, possibly in systemic inflammation, likely in chronic neuroinflammation and possibly in low level neuroinflammation. The latter may include subgroups of psychiatric disorders. PCOP associated pathomechanisms might explain for example the surprising muscle involvement in depression and schizophrenia, or diffuse pain or dysautonomia. PCOP associated pathomechanisms should generally relate to PCOP anatomy and the CSF outflow physiology respectively pathophysiology.

Pro- and anti-inflammatory cytokines expression in rat's brain and spleen exposed to chronic mild stress: Involvement in depression

The association between pro-inflammatory cytokines and depression has been reported by many studies. However, the mechanisms by which inflammation affects mood are only partially understood. In this study, we detected depression-like behavior in a rat animal model which was induced inflammation in the spleen and brain by chronic mild stress (CMS). Wistar rats receiving CMS treatment for four weeks showed a variety of depression-like behavioral changes, including a significant reduction in sucrose preference and locomotion. Real-time RT-PCR was used to analyze the transcriptional regulation of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-18) and anti-inflammatory cytokines (IL-10, IL-4 and TGF-β) in hippocampus, cortex, hypothalamus and spleen. The result showed high expression of pro-inflammatory cytokines IL-1β, TNF-α and IL-6, and low expression of anti-inflammatory cytokines TGF-β and IL-10, thus higher ratio of TNF-α/IL-10 and IL-6/IL-10 in the brain of animal exposed to CMS. Simultaneously, brain derived neurotrophic factor mRNA decreased significantly in the hippocampus and hypothalamus of stressed rats. Immunofluorescence found that the BrdU Positive cells after CMS treatment significantly decreased in the hippocampus. These data suggested a crucial role of dysregulation between pro- and anti-inflammatory in CMS-induced depression, possibly because the imbalance of cytokines affects regeneration of neurons.